Method for treating cancer

ABSTRACT

A method for treating a cancer. The cancer excluding an adenocarcinoma and being epithelioma, glioma, sarcoma, melanoma, lymphoma or leukemia; or the cancer is an adenocarcinoma cancer excluding colon cancer, lung cancer and gastric cancer. The method comprises administering to a subject in need thereof and suffering from cancer, a pharmaceutically effective amount of at least one sulfoquinovosylacylglycerol compound represented by formula (1):  
                 
 
     wherein R 101  represents an acyl residue of an unsaturated fatty acid and R 102  represents a hydrogen atom and/or at least one pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a Divisional Application of application Ser. No.09/934,874 filed Aug. 22, 2001, which is a Continuation-in-PartApplication of PCT Application No. PCT/JP00/00973, filed Feb. 21, 2000,which was not published under PCT Article 21(2) in English. The entirecontents of U.S. application Ser. No. 09/934,874 and Internationalapplication PCT/JP00/00973 are hereby incorporated by reference herein.

[0002] This application is based upon and claims the benefit of priorityfrom the prior Japanese Patent Application No. 11-051397, filed Feb. 26,1999, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The present invention relates to a medicament containing at leastone compound selected from the group consisting ofsulfopyranosylacylglycerol derivatives and pharmaceutically acceptablesalts thereof, as an active ingredient.

[0005] 2. Description of the Related Art

[0006] Sulfur-containing glycolipids contained in natural productsderived from, e.g., algae and higher plants are known to havephysiological activities.

[0007] For example, in a document of Ohta et al. (Chemical &Pharmaceutical Bulletin, 46(4), (1998)), it is described that a specificsulfoquinovosyldiacylglycerol derivative derived from red algae,Gigartina tenella, exhibits not only inhibitory activities against DNApolymerases α and β of higher organisms but also an HIV-derivedreverse-transcriptase inhibitory activity. Thesulfoquinovosyldiacylglycerol derivative disclosed in the Ohta documentis the one whose fatty acid that bonded, through ester-bond, at the C1carbon atom of the glycerol is an unsaturated fatty acid having 20carbon atoms with 5 double bonds, and whose another fatty acid thatbonded at the C2 carbon atom of the glycerol is a saturated fatty acidhaving 16 carbon atoms.

[0008] Furthermore, in a document of Mizushina et al. (BiochemicalPharmacology 55, 537-541 (1998)), it is described that a mixture ofspecific sulfoquinovosyldiacylglycerol derivatives derived from apteridophyte exhibits inhibitory activities against a calf DNApolymerase α and a rat DNA polymerase β, however, the mixture has noeffect upon an HIV-derived reverse-transcriptase activity.

[0009] On the other hand, in a document of Sahara et al. (BritishJournal of Cancer, 75(3), 324-332 (1997)), it is described that afraction of sulfoquinovosylmonoacylglycerols contained in an acetoneextract from a sea urchin intestine exhibits anticancer activitiesin-vivo and in-vitro. However, the sulfoquinovosylmonoacylglycerolfraction for which Sahara found the anticancer activities principallycontains sulfoquinovosylmonoacylglycerol having, bonded thereto throughan ester-bond, a saturated fatty acid with 16 carbon atoms. In thesulfoquinovosylmonoacylglycerol fraction,sulfoquinovosylmonoacylglycerols whose acyl moiety is that of anunsaturated fatty acid, are contained only in an extremely small amount.In addition, Sahara et al. have not yet investigated on anticanceractivities with respect to individual components contained in thesulfoquinovosylmonoacylglycerol mixture.

[0010] Furthermore, National Patent Publication No. 5-501105 describesthat a sulfoquinovosyldiacylglycerol derivative has an anti-virusactivity. More specifically, it discloses that the derivative has ananti-HIV (human immunodeficiency virus) activity, however it does notdisclose that the derivative has DNA polymerase inhibitory activitiesand anticancer activities.

BRIEF SUMMARY OF THE INVENTION

[0011] An object of the present invention is to provide a medicamentcontaining a sulfopyranosylacylglycerol derivative as an activeingredient.

[0012] The present inventors found that specificsulfopyranosylacylglycerol derivatives have medicinal activities andachieved the present invention. The present invention provides amedicament containing, as an active ingredient, at least one compoundselected from the group consisting of:

[0013] compounds represented by the following General Formula (1):

[0014]  wherein R₁₀₁ represents an acyl residue of an unsaturated higherfatty acid, and R₁₀₂ represents a hydrogen atom or an acyl residue of anunsaturated higher fatty acid; and

[0015] pharmaceutically acceptable salts thereof.

[0016] Additional objects and advantages of the invention will be setforth in the description which follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention may be realized and obtained bymeans of the instrumentalities and combinations particularly pointed outhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings, which are incorporated in andconstitute a part of the specification, illustrate embodiments of theinvention, and together with the general description given above and thedetailed description of the embodiments given below, serve to explainthe principles of the invention.

[0018]FIG. 1 shows anticancer activities of medicaments of the presentinvention against tumor cells.

[0019]FIG. 2 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

[0020]FIG. 3 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

[0021]FIG. 4 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

[0022]FIG. 5 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

[0023]FIG. 6 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

[0024]FIG. 7 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

DETAILED DESCRIPTION OF THE INVENTION

[0025] In the specification, the term “carbon atoms” of a protectinggroup refers to the number of carbon atoms assuming that the protectinggroup is unsubstituted. To be more specific, when the group representedby R⁶ is a substituted alkyl group, its number of carbon atoms is thatof the alkyl group itself, and the number of carbon atoms of thesubstituent on the alkyl group is not counted. The same conditions areapplicable to the case where the protecting group is other than thealkyl group.

[0026] First, the sulfopyranosylacylglycerol derivative represented byGeneral Formula (1) and contained in the medicament of the presentinvention as an active ingredient will be more specifically explained.

[0027] In the sulfopyranosylacylglycerol derivative represented byGeneral Formula (1), the pyranose, which is a sugar skeletonconstituting the pyranoside, may include α-D-quinovose (i.e.,6-deoxy-α-D-glucose), β-D-quinovose (i.e., 6-deoxy-β-D-glucose),α-D-fucose (i.e., 6-deoxy-α-D-galactose), β-D-fucose (i.e.,6-deoxy-β-D-galactose), α-D-rhamnose (i.e., 6-deoxy-α-D-mannose) andβ-D-rhamnose (i.e., 6-deoxy-β-D-mannose).

[0028] The absolute configuration of the carbon (asymmetric carbon) atthe 2-position of the glycerol moiety may be either the S- orR-configuration.

[0029] The sugar skeleton of the pyranoside may be either a boat orchair configuration. However, the chair configuration is preferable inview of stability.

[0030] In the sulfopyranosylacylglycerol derivative represented byGeneral Formula (1), R₁₀₁ represents an acyl residue of an unsaturatedhigher fatty acid.

[0031] The fatty acid giving the acyl residue represented by R₁₀₁ may bea straight-chain or branched-chain, unsaturated higher fatty acid. Fromthe viewpoint of using the compound represented by General Formula (1)as a medicament, the straight-chain unsaturated higher fatty acid ispreferably used.

[0032] The acyl residue of the straight-chain unsaturated higher fattyacid has 14-26 carbon atoms (preferably even number of 14-26) with 1-6unsaturated bonds. The acyl residue of the straight-chain unsaturatedhigher fatty acid is represented by Formula: R—C (═O)—, where R is astraight-chain aliphatic unsaturated hydrocarbon group of 13-25 carbonatoms (preferably, an odd number of 13-25), and 1-6 unsaturated bondsare included in the hydrocarbon group.

[0033] In the sulfopyranosylacylglycerol derivative represented byGeneral Formula (1), R₁₀₂ represents a hydrogen atom or an acyl residueof an unsaturated higher fatty acid. In particular, R₁₀₂ preferablyrepresents a hydrogen atom in consideration of an anti-cancer activity.When R₁₀₂ is an acyl residue of the unsaturated higher fatty acid, thesame fatty acid giving an acyl residue as defined in R₁₀₁ may beselected. R₁₀₁ and R₁₀₂ may be the same or different acyl residue.

[0034] Now, a method of preparing the sulfopyranosylacylglycerolderivatives of the present invention will be explained below.

[0035] The sulfopyranosylacylglycerol derivatives of the presentinvention can be prepared via (Step A) to (Step J) in accordance withthe reaction procedure shown in Scheme 1 below:

[0036] (Step A) The hydroxyl group bonded to the C1 carbon of thepyranose is converted into a 2-propenyl group. (Step B) The hydroxylgroup of the C6 carbon of the pyranose is protected. (Step C) Thehydroxyl groups bonded to the C2, C3 and C4 carbons of the pyranose areprotected. (Step D) The protecting group of the C6 carbon previouslyprotected is deprotected. (Step E) The hydroxyl group bonded to the C6carbon is substituted with a group (for example, an alkylsulfonyloxygroup or arylsulfonyloxy group) which can be converted to a carbonylthiogroup. (Step F) The C6 carbon is converted into a carbonylthio group.(Step G) The 2-propenyl group bonded to the C1 carbon is converted intoa diol. (Step H) Both of the hydroxyl groups or only the hydroxyl groupat the 1-position of the diol thus obtained are/is esterified with adesired unsaturated higher fatty acid. (Step I) The carbonylthio groupat the C6 carbon is converted into a sulfonate salt. (Step J) Theprotecting groups of C2, C3 and C4 carbons of the sulfonate saltobtained are deprotected. As a result, a salt of asulfopyranosylacylglycerol derivative of the present invention can beproduced. The salt thus obtained is subjected to titration with an acidsuch as hydrochloric acid to give the sulfopyranosylacylglycerolderivative of the present invention.

[0037] The aforementioned Steps A-J will be further explained in detail.

[0038] In Step A, the 2-propenylation is carried out by reacting thepyranose with allyl alcohol in the presence of a strong acid, such astrifluoromethanesulfonic acid, usually at room temperature to 100° C.,preferably from 80 to 90° C., for a half day to two days. However, thereaction time varies depending upon the reaction conditions.

[0039] In Step B, the hydroxyl group bonded to the C6 carbon isprotected to obtain the compound to which —OR⁶ is bonded at the C6carbon (where R⁶ represents an alkyl or substituted silyl group).

[0040] As the compound capable of protecting the hydroxyl group, acompound can be used which can provide an alkyl group or substitutedsilyl group as the R⁶ group.

[0041] Examples of the alkyl group represented by R⁶ preferably includebulky and substituted alkyl groups. The substituents of the bulky andsubstituted alkyl groups include methyl and phenyl groups. The specificexamples of the substituted alkyl group include t-butyl and tritylgroups.

[0042] When the group represented by R⁶ represents a substituted silylgroup, examples of substituents of the substituted silyl group includelower alkyl groups, preferably alkyl groups having 1-4 carbon atoms (forexample, methyl, ethyl, isopropyl and t-butyl groups); and aryl groups,preferably aryl groups having 6 carbon atoms (for example, a phenylgroup). The substituted silyl group represented by R⁶ preferablyincludes tri-substituted silyl groups, more preferably, at-butyldiphenylsilyl group.

[0043] When the compound 3, where R⁶ represents an alkyl group, is to beobtained, the protection of the hydroxyl group in Step B can be carriedout by adding a compound represented by R⁶—X (where R⁶ represents thealkyl group defined above, and X represents a halogen atom such aschlorine atom) to a solution of the compound 2 dissolved in an organicsolvent, such as anhydrous pyridine, and reacting the solution mixtureat room temperature in the presence of a catalyst such asp-dimethylaminopyridine (DMAP). As the compound R⁶—X, trityl chloride ispreferably used in view of manufacturability and reactivity.

[0044] When the compound 3, where R⁶ represents a substituted silylgroup, is to be obtained, t-butyldiphenylsilyl chloride, for example, isused as the compound R⁶—X, and the reaction is carried out usually inthe presence of a catalyst, such as imidazol, at room temperature for ahalf day to two days. Note that the reaction time varies depending uponthe reaction conditions.

[0045] In Step C, the hydroxyl groups bonded to the C2, C3 and C4carbons are protected and converted into —OR¹, —OR² and —OR³,respectively, where R¹ to R³ independently represent an alkyl orsubstituted silyl group. The protection of these hydroxyl groups can becarried out by activating, with sodium hydride, the hydroxyl groupsbonded to the C2, C3 and C4 carbons of the compound 3 dissolved in anorganic solvent, such as N,N-dimethylformamide (DMF), and reacting withthe compound capable of protecting these hydroxyl groups at roomtemperature.

[0046] As the compound capable of protecting the hydroxyl groups, benzylbromide, p-methoxybenzyl bromide, t-butyldimethylsilyl chloride ortriethylsilyl chloride may be used.

[0047] The reaction using the compound capable of protecting thehydroxyl groups can be carried out under a suitable reaction conditionfor each of the protecting groups.

[0048] The deprotection of the protecting group bonded to the C6 carbonin Step D may be carried out by reacting a solution of the compound 4dissolved in an organic solvent, such as methanol, in the presence of acatalyst, such as p-toluenesulfonic acid, generally for 12 hours to oneday at room temperature. The reaction time varies depending upon thereaction conditions.

[0049] In Step E, R⁴, that is, an alkylsulfonyl or arylsulfonyl group isbonded to the hydroxyl group at the C6 carbon of the compound 5, so thatthe hydroxyl group is converted into —OR⁴ to give the compound 6.

[0050] The reaction to give the —OR⁴ group is performed by adding acompound having the alkylsulfonyl group or a compound having thearylsulfonyl group to a solution of the compound 5 dissolved in anorganic solvent, and reacting them. The alkyl group of the compoundhaving the alkylsulfonyl group preferably includes unsubstituted alkylgroups, more preferably, lower alkyl groups, much more preferably, alkylgroups having 1-2 carbon atoms (methyl and ethyl groups). The compoundhaving an alkylsulfonyl group can be represented by R⁴, —X (where R⁴′represents an alkylsulfonyl group, and X represents a halogen atom).Specific examples include methanesulfonyl chloride and ethanesulfonylchloride.

[0051] On the other hand, the aryl group of the compound having thearylsulfonyl group may include unsubstituted and substituted arylgroups, preferably aryl groups having 6 carbon atoms (e.g., a phenylgroup). In the case of the substituted aryl group, examples of thesubstituent thereof include p-methyl and p-methoxy groups. Examples ofthe compound having an arylsulfonyl group include compounds representedby R⁴″—X (where R⁴″ represents an arylsulfonyl group, and X represents ahalogen atom). Specific examples include p-toluenesulfonyl chloride,p-methoxybenzenesulfonyl chloride and benzenesulfonyl chloride.

[0052] Of the compounds having an alkylsulfonyl or arylsulfonyl group, acompound having a tosyl group is preferably used from the viewpoint ofreaction facility.

[0053] In the reaction of Step E, as an organic solvent, pyridine ordichloromethane may be used.

[0054] The reaction mentioned above may be performed, as the case maybe, in the presence of a catalyst, such as DMAP, at room temperature for2 hours to one day. The reaction time varies depending upon the reactionconditions.

[0055] In Step F, the sulfonyloxy group (—OR⁴) of the compound 6 isreplaced with a carbonylthio group represented by —SC(═O)R⁵, where R⁵represents a hydrogen atom, an alkyl or aryl group.

[0056] In the reaction, a compound capable of substituting thealkylsulfonyloxy or arylsulfonyloxy group of the compound 6 with thecarbonylthio group, is allowed to react in an organic solvent to give acompound 7. Hereinafter, this compound will be referred to as“O-substituted→S-substituted compound”.

[0057] Examples of the O-substituted→S-substituted compound includealkali metal salts and alkali earth metal salts of a thiocarboxylicacid. Examples of the thiocarboxylic acid include thioformic acid, lowerthiocarboxylic acids, preferably aliphatic thiocarboxylic acids eachhaving 1-5 carbon atoms in its aliphatic hydrocarbon moiety (forexample, thioacetic acid or thiopropionic acid), and aromaticthiocarboxylic acids each having 6-10 carbon atoms in its aromatichydrocarbon moiety (for example, thiobenzoic acid).

[0058] The alkali metal that forms a salt with the thiocarboxylic acidincludes potassium and sodium. The alkali earth metal includes magnesiumand calcium.

[0059] Of the above-mentioned O-substituted→S-substituted compounds,salts of thioacetic acid may be preferably used since a reaction canproceed stably and the sulfur atom can be easily oxidized in a laterstep.

[0060] Examples of an organic solvent used in the reaction includealcohols, preferably lower alcohols, (for example, methanol, ethanol andpropanol), N,N-dimethylformamide and dimethylsulfoxide.

[0061] The aforementioned reaction may be performed usually at roomtemperature to the boiling point of a solvent to be used while stirringfor one hour to one day. Note that the reaction time varies dependingupon the reaction conditions.

[0062] The dihydroxylation of Step G may be performed by adding anoxidizing agent, such as osmium tetraoxide, to a solution of thecompound 7 dissolved in a solvent mixture, such as a mixture oft-butanol and water, and then reacting the resultant mixture in thepresence of a re-oxidizing agent, such as trimethylamine N-oxide, atroom temperature for one hour to one day. Note that the reaction timevaries depending upon the reaction conditions.

[0063] By the esterification of Step H, a sulfopyranosylacylglycerolderivative having a desired unsaturated higher fatty acid bonded,through an ester-bond, to its glycerol moiety can be obtained.

[0064] This reaction can be carried out by adding an unsaturated higherfatty acid corresponding to a final product to a solution of thecompound 8 dissolved in a suitable organic solvent, such asdichloromethane, and then reacting the resultant mixture, if necessary,in the presence of a suitable catalyst, such asethyldimethylaminopropylcarbodiimide (EDCI)-DMAP.

[0065] In the reaction of Step H, as the fatty acid to be added, use maybe made of an unsaturated higher fatty acid whose acyl group is thatrepresented by R₁₀₁ of General Formula (1).

[0066] In the reaction of Step H, the compound 9 is obtained in the formof a mixture of a diacylester and a monoacylester. The diacylesterherein is represented by Formula (1) of the present invention where eachof R₁₀₁ and R₁₀₂ is an acyl residue of the unsaturated higher fatty acidadded. The monoacylester herein has the acyl residue of the unsaturatedhigher fatty acid added, as the R₁₀₁ only. Two or more unsaturatedhigher fatty acids may be added, if desired, in the reaction of Step H.In this case, the resultant mixture contains diacylesters represented byGeneral Formula (1) where R₁₀₁ and R₁₀₂ are the same or different acylresidues, and monoesters having different acyl residues as R₁₀₁.

[0067] If necessary, the mixture of the monoesters and diesters can beisolated from each other by, for example, chromatography, and subjectedto the next reaction Step I.

[0068] Furthermore, if desired, by reacting a monoester obtained in StepH with a fatty acid having a different acyl residue from the acylresidue (R₁₀₁) of the monoester, it is possible to obtain a diesterwhere R₁₀₂ and R₁₀₁ are different acyl residues. This additionalesterification step may be performed under the same conditions as thoseof Step H except that a different fatty acid is used.

[0069] In Step I, the conversion into a sulfonate salt can be carriedout by adding an oxidizing agent, such as OXONE (2 KHSO₅+KHSO₄+K₂SO₄) ormolybdenum oxidizing agent (for example, hexaammonium heptamolybdate),into a solution of the compound 9 dissolved in an organic solvent, whichis buffered with acetic acid and potassium acetate, and then allowingthe resultant mixture to react at room temperature.

[0070] The deprotection of the protecting groups bonded to carbons atthe C2 to C4 carbons in Step J can be carried out by a method suitablefor a protecting group to be used and capable of maintaining a doublebond of the unsaturated fatty acid. For example, when the protectinggroup is a silyl group, deprotection can be made by using acid catalyst(e.g., trifluoroacetic acid).

[0071] Note that the pyranosyl moiety of a starting material usuallytakes α- and β-anomer configurations in a solution. Therefore, theproduct in each step results in a mixture of α- and β-anomers. Themixture is separated into α- and β-anomers by chromatography.Furthermore, depending upon a type of the sugar, it is helpful to carryout a benzilydenation after Step A, thereby to separate an anomer bycrystallization.

[0072] Now, we will explain the medicament of the present inventioncontaining at least one compound selected from the group consisting ofsulfopyranosylacylglycerol derivatives of the present invention andpharmaceutically acceptable salts thereof, as an active ingredient.

[0073] The sulfopyranosylacylglycerol derivative serving as an activeingredient for the medicament of the present invention may be an isomerhaving quinovose, rhamnose or fucose as the pyranose constituting thepyranosyl moiety. The derivative may be an isomer in which the pyranosylmoiety is bonded to glyceridyl moiety with an α- or β-configuration. Thederivative may be an isomer regarding the asymmetric carbon at the C2carbon of the glyceridyl moiety. The medicament of the present inventionmay include one of these isomers alone or in combination of two or moreisomers as long as they do not adversely affect the activity.

[0074] In the present invention, the medicinal use includes a DNApolymerase inhibitor and an anticancer agent.

[0075] Examples of the pharmaceutically acceptable salts employed in themedicament of the present invention include, but not limited to, a saltof a monovalent cation such as a sodium or potassium ion. Hereinafter,the compounds of the group consisting of sulfopyranosylacylglycerolderivatives and pharmaceutically acceptable salts thereof are sometimesreferred to as “medicinally active substance of the present invention”.

[0076] The medicinally active substance of the present invention can beorally or parenterally administered. Medicinally active substance of thepresent invention can be combined with, for example, a pharmaceuticallyacceptable excipient or diluent depending on an administration routethereby to form a medicinal formulation.

[0077] The forms of the agent suitable for oral administration include,solid-, semi-solid, liquid- and gas-states. Specific examples include,but not limited to, tablet, capsule, powder, granule, solution,suspension, syrup and elixir agents.

[0078] In order to formulate the medicinally active substance of thepresent invention into tablets, capsules, powders, granules, solutionsor suspensions, the substance is mixed with a binder, a disintegratingagent and/or a lubricant, and, if necessary, the resultant is mixed witha diluent, a buffer, a wetting agent, a preservative and/or a flavor, bya known method. Examples of the binder include crystalline cellulose,cellulose derivatives, cornstarch and gelatin. Examples of thedisintegrating agent include cornstarch, potato starch and sodiumcarboxymethylcellulose. Examples of the lubricant include talc andmagnesium stearate. Furthermore, additives such as lactose and mannitolmay also be used as long as they are used conventionally.

[0079] Moreover, the medicinally active substance of the presentinvention may be administered in the form of aerosol or inhalant, whichis prepared by charging the active substance of liquid- or finepowder-form, together with a gaseous or liquid spraying agent, and, ifnecessary, a known auxiliary agent such as a wetting agent, into anon-pressurized container such as an aerosol container or a nebulizer.As the spraying agent, a pressurized gas, for example,dichlorofluoromethane, propane or nitrogen may be used.

[0080] For parenteral administration, the medicinally active agent ofthe present invention can be injected by, for example, rectaladministration or injection.

[0081] For rectal administration, a suppository may be used. Thesuppository may be prepared by mixing the medicinally active substanceof the present invention with an excipient that can be melted at bodytemperature but is solid at room temperature, such as cacao butter,carbon wax or polyethylene glycol, and molding the resultant material,by a known method.

[0082] For the administration by injection, the medicinally active agentof the present invention can be injected hypodermically,intracutaneously, intravenously or intramuscularly. An injectionpreparation may be formulated by dissolving, suspending or emulsifyingthe medicinally active substance of the invention into an aqueous ornon-aqueous solvent such as a vegetable oil, a synthetic glyceride witha fatty acid, an ester of a higher fatty acid or propylene glycol by aknown method. If desired, a conventional additive such as a solubilizingagent, an osmoregulating agent, an emulsifier, a stabilizer or apreservative, may be added to the preparation.

[0083] For formulating the medicinally active substance of the inventioninto solutions, suspensions, syrups or elixirs, a pharmaceuticallyacceptable solvent such as sterilized water for injection or normalizedphysiological saline solution may be used.

[0084] The medicinally active substance of the invention may be usedtogether with a pharmaceutically acceptable compound having anotheractivity, to prepare a medicinal preparation.

[0085] The dose of the medicinally active substance of the presentinvention may be appropriately set or adjusted in accordance with anadministration form, an administration route, a degree or stage of atarget disease, and the like. For example, in the case of oraladministration, a dose of the medicinally active substance may be set at1-10 mg/kg body weight/day. In the case of administration by injection,a dose of the medicinally active substance may be set at 1-5 mg/kg bodyweight/day. In the case of rectal administration, a dose of themedicinally active substance may be set at 1-5 mg/kg body weight/day.However, the dose is not limited to these.

[0086] When the medicinally active substance of the present invention isused as an anticancer agent, examples of cancers to be treated includethose having features of malignant tumors such as solid tumors includingadenocarcinoma, epithelioma, sarcoma, glioma, melanoma and lymphoma, anda fluid cancer such as leukemia.

EXAMPLES

[0087] The present invention will now be described by way of itsExamples. However, the present invention is not limited to theseExamples.

Synthesis Example

[0088] Preparation steps of a sulfopyranosylacylglycerol derivative willbe shown in Scheme 2 by way of a sulfoquinovosylacylglycerol αderivative.

[0089] Ts=tosyl, TBDMS=t-butyldimethylsilyl, AcS=acetylthio,

[0090] R₁₀₁=an acyl residue of an unsaturated higher fatty acid, and

[0091] R₁₀₂=a hydrogen atom or an acyl residue of an unsaturated higherfatty acid.

[0092] Reaction Conditions:

[0093] a; allyl alcohol, trifluoromethanesulfonic acid, at 80° C.

[0094] m; benzaldehyde, zinc chloride, at room temperature

[0095] n; acetic acid, water, at 100° C.

[0096] p; toluenesulfonyl chloride, dimethylaminopyridine, pyridine, atroom temperature

[0097] q; t-butyldimethylsilyl trifluoromethanesulfonate, 2,6-lutidine,dichloromethane, at room temperature

[0098] f; potassium thioacetate, ethanol, under reflux

[0099] g; osmium tetraoxide, trimethylamine N-oxide dihydrate,t-butanol, water

[0100] h; fatty acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDCI), at room temperature

[0101] i; OXONE, glacial acetic acid, potassium acetate, at roomtemperature

[0102] j; acetic acid, tetrahydrofuran, trifluoroacetic acid, water, atroom temperature

[0103] Scheme 2 is the same as those of Scheme 1 except for Steps B to Eof Scheme 1. More specifically, in Scheme 2, Step m is employed insteadof Step B in Scheme 1. In Step m, compound (II) is reacted withbenzaldehyde to prepare a benzylidene derivative. By virtue of thisreaction, α-anomer is crystallized and separated.

[0104] In the reaction of Scheme 2, p-toluenesulfonyl chloride isreacted with compound (IV) thereby to bond a tosyl group at C6 carbonthereof in Step p, and then, the C2, C3 and C4 carbons are protectedwith t-butyldimethylsilyl groups (Step q). In this case, Step B ofprotecting the C6 carbon by an alkyl or substituted silyl group, andStep D of deprotecting the C6 carbon in the process of Scheme 1 may beomitted, because of the stable nature of the tosyl group.

[0105] Furthermore, in Step h, a mixture of a monoester and diester isobtained. The monoester and the diester are separated from each other bychromatography and subjected to Step i, respectively.

Example 1

[0106] Route a: 1-O-(2-propenyl)-D-glucose (II)

[0107] One hundred grams of D-glucose (I) was added into 250 mL of allylalcohol and sufficiently dissolved therein. To the solution, 0.8 mL oftrifluoromethanesulfonic acid was gradually added under an ice-cooledcondition. Then, the solution was reacted in an oil bath at 80° C. for30 hours while stirring. At the stage where the reaction sufficientlyproceeded, the reaction mixture was neutralized with 1 mL oftrimethylamine and concentrated in vacuo. The thin layer chromatographydemonstrated a yield of about 60-70%.

[0108] Route m: 1-O-(2-propenyl)-4,6-o-benzylidene-α-D-glucose (III)

[0109] 37.5 grams of the compound (II) was added to 210 mL ofbenzaldehyde and dissolved well. To the solution, 98 g of zinc chloridewas added. The reaction mixture was reacted at room temperature for 4hours. Thereafter, the reaction mixture was added to 500 mL of hexane,and then 100 mL of diluted sodium hydrogencarbonate was added. Thereaction mixture was allowed to stand at 0° C. for 30 minutes tocrystallize. The crystal was filtered with suction, and dissolved in 50mL of ethanol. The solution was allowed to stand at 0° C. for 30 minutesfor recrystallization (yield: 21 g (68.1 mmol), recovery: 40.0%).

[0110]¹H NMR (300 MHz, CDCl₃+TMS); 7.51-7.49 (2H, m, Ar), 7.38-7.33 (3H,m, Ar), 5.98-5.85 (1H, m, —CH═CH₂), 5.51 (1H, s, Ar—CH), 5.31 (1H, dd,J=1.5&15.9, —CH═CH ₂), 5.23 (1H, dd, J=1.2&10.4, —CH═CH ₂), 4.90 (1H, d,J=3.9, H-1), 4.28-4.19 (2H, m, —CH₂ —CH═CH₂), 4.06-4.00 (1H, m, H-5),3.93 (1H, t, J=9.3, H-3), 3.87-3.78 (1H, m, H-6a), 3.70 (1H, t, J=10.2,H-2), 3.60 (1H, dd, J=3.8&9.2, H-6b), 3.47 (1H, t, J=9.3, H-4)

[0111] Route n: 1-O-(2-propenyl)-α-D-glucose (IV)

[0112] Into 260 mL of a solution of acetic acid and water (8:5), 10.7 g(34.7 mmol) of the compound (III) was dissolved. The solution wasreacted at 100° C. for 1 hour, concentrated in vacuo, and purified bysilica gel flash chromatography (dichloromethane:methanol=6:1) (yield:6.3 g (28.6 mmol), recovery: 82.4%).

[0113]¹H NMR (300 MHz, CD₃OD+TMS); 5.92-5.79 (1H, m, —CH═CH₂), 5.26-5.18(1H, m, —CH═CH ₂), 5.07-5.03 (1H, m, —CH═CH ₂), 4.23-3.23 (7H, m)

[0114] Route p: 1-O-(2-propenyl)-6-O-(4-tolylsulfonyl)-α-D-glucose (V)

[0115] Into 200 mL of anhydrous pyridine, 6.3 g (28.6 mmol) of thecompound (IV) was dissolved, and 195 mg of p-dimethylaminopyridine(DMAP) and 7.0 g of p-toluenesulfonyl chloride were added. The solutionwas reacted for 16 hours at room temperature while stirring. Thereafter,the reaction was quenched by adding 20 mL of cold distilled water, andthe reaction mixture was extracted with ethyl acetate (3×200 mL). Theorganic layers were combined, neutralized to pH 4 with 1.0 M and 0.1 Mhydrochloric acids, washed with brine (2×200 mL), dried over anhydroussodium sulfate, filtered, concentrated in vacuo, and purified by silicagel flash chromatography (dichloromethane:methanol=20:1) (yield: 8.6 mg(23.0 mmol), recovery: 83.8%).

[0116]¹H NMR (300 MHz, CDCl₃+TMS); 7.77 (2H, d, J=8.3, Ar at TsCH₃),7.30 (2H, d, J=8.1 Ar at TsSO₂), 5.90-5.77 (1H, m, —CH═CH₂), 5.24 (1H,dd, J=1.4&17.2, —CH═CH ₂), 5.11 (1H, dd, J=1.2&12.4, —CH═CH ₂), 4.79(1H, d, J=3.3, H-1), 4.38-3.38 (8H, m), 2.40 (3H, s, TSCH₃ )

[0117] Route q:2,3,4-tri-O-(t-butyldimethylsilyl)-1-O-(2-propenyl)-6-O-(4-tolylsulfonyl)-α-D-glucose(VI)

[0118] Into 25 mL of anhydrous dichloromethane, 11.2 g (29.9 mmol) ofthe compound (V) was dissolved and 23.8 g of t-butyldimethylsilyltrifluoromethanesulfonate and 14.4 g of 2,6-lutidine were added. Thesolution was reacted under nitrogen flow for 16 hours while stirring.Thereafter, the reaction was quenched by adding 150 mL ofdichloromethane, and the reaction mixture was washed with brine (2×100mL), dried over anhydrous sodium sulfate, filtered, concentrated invacuo, purified by silica gel flash chromatography (hexane:ethylacetate=30:1) (yield: 19.6 g (27.4 mmol), recovery: 91.6%).

[0119]¹H NMR (300 MHz, CDCl₃+TMS); 7.83 (2H, d, J=8.3, Ar at TsCH₃),7.29 (2H, d, J=8.0, Ar at TsSO2), 5.92-5.79 (1H, m, —CH═CH₂), 5.21 (1H,dd, J=1.5&17.2, —CH═CH ₂), 5.11 (1H, d, J=10.4, —CH═CH ₂), 4.67 (1H, d,J=2.8, H-1), 4.30-3.44 (8H, m), 2.41 (3H, s, TSCH₃ ), 0.91-0.78 (27H, m,CH₃ at t-Bu), 0.13-−0.02 (18H, m, Si—CH₃ )

[0120] Route f:2,3,4-tri-O-(t-butyldimethylsilyl)-1-O-(2-propenyl)-6-deoxy-6-acetylthio-α-D-glucose(VII)

[0121] Into 20 mL of anhydrous ethanol, 7.9 g (11.0 mmol) of thecompound (VI) was dissolved, and then 1.8 g of potassium thioacetate wasadded. The solution was reacted under reflux for 3 hours while stirring.Thereafter, the reaction was quenched by adding 100 mL of cold distilledwater, and the reaction mixture was extracted with ethyl acetate (3×200ml). The organic layers were combined, washed with brine (2×200 mL),dried over anhydrous sodium sulfate, filtered, concentrated in vacuo,and purified by silica gel flash chromatography (hexane:ethylacetate=50:1) (yield: 5.6 g (9.02 mmol), recovery: 82.0%).

[0122]¹H NMR (300 MHz, CDCl₃+TMS); 5.97-5.81 (1H, m, —CH═CH₂), 5.26 (1H,dd, J=1.6&17.2, —CH═CH ₂), 5.13 (1H, dd, J=1.6&10.4, —CH═CH ₂), 4.73(1H, d, J=3.2, H-1), 4.32-3.42 (7H, m), 2.83 (1H, dd, J=9.8&13.3, H-6b),2.30 (3H, s, SCOCH₃ ), 0.91-0.82 (27H, m, CH₃ at t-Bu), 0.12-−0.03 (18H,m, Si—CH ₃)

[0123] Route g:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-glycerol(VIII)

[0124] Into a mixture of t-butanol:H₂O (=4:1), 5.6 g (9.02 mmol) of thecompound (VII) was dissolved and then 1.5 g of trimethylamine N-oxidedihydrate and 15 mL of 0.04 M solution of osmium tetraoxide in t-butanolwere added. The solution was reacted at room temperature for 22 hourswhile stirring. Thereafter, 15 g of activated charcoal was added, andthe reaction mixture was allowed to stand while stirring for 1.5 hoursto adsorb the osmium tetraoxide. After filtration with suction, thereaction was quenched by adding 200 mL of cold distilled water, andextracted with ethyl acetate (3×200 mL). The organic layers werecombined, washed with brine (2×300 mL), dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo, and purified by silica gelflash chromatography (hexane:ethyl acetate=3:1→2:1) (yield: 5.2 g (7.94mmol), recovery: 88.0%).

[0125]¹H NMR (300 MHz, CDCl₃+TMS); 4.73 (1H, m, H-1 (R and S)),4.12-3.40 (10H, m), 2.86 (1H, dd, J=9.2&13.6, H-6b), 2.32 (3H, s, SCOCH₃), 0.88-0.79 (27H, m, CH₃ at t-Bu), 0.08-−0.03 (18H, m, Si—CH₃ )

[0126] Route h:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-1-O-oleoyl-glycerol(IX) and3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-1,2-di-O-oleoyl-glycerol(IX′)

[0127] Into 20 mL of anhydrous dichloromethane, 1.37 g (2.09 mmol) ofthe compound (VIII) was dissolved and then 600 mg of EDCl, 26 mg of DMAPand 660 mg of oleic acid were added. The solution was reacted at room 25temperature for 16 hours while stirring. Thereafter, the reaction wasquenched by adding 200 mL of dichloromethane, and washed with brine(2×100 mL), dried over anhydrous sodium sulfate, filtered, concentratedin vacuo, and purified by silica gel flash chromatography (hexane:ethylacetate=20:1→10:1→7:1) (yield of the diester: 772 mg (652 μmol) andyield of the monoester: 895 mg (974 μmol); recovery (both esters intotal) of 78.0%).

[0128]¹H NMR (300 MHz, CDCl₃+TMS); 5.32-5.28 (2H, m, —CH═CH—), 4.68 (1H,m, H-l (R and S)), 3.98-3.36 (10H, m), 2.81 (1H, dd, J=9.5 & 13.4,H-6b), 2.32-2.27 (5H, m, OCOCH₂ & SCOCH₃ ), 1.98-1.93 (4H, m, CH₂—CH═CH—CH₂ ), 1.61-1.56 (2H, m, OCOCH₂CH₂ ), 1.28-1.23 (20H, br, —CH₂—), 0.88-0.79 (30H, m, CH₃ at t-Bu & CH₃ at Acyl), 0.09-−0.04 (18H, m,Si—CH₃ )(NMR of the monoester)

[0129] Route i:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-sulfo-α-D-glucopyranosyl]-1-O-oleoyl-glycerolSodium Salt (X)

[0130] Into 3.5 mL of glacial acetic acid, 21.4 mg (23.2 μmol) of thecompound (IX: monoester) was dissolved and then 500 mg of potassiumacetate and 35.4 mg of OXONE were added. The mixture was reacted at roomtemperature for 6 hours while stirring. Thereafter, the reaction wasquenched by adding 15 mL of cold distilled water, extracted with ethylacetate (5×20 mL). The organic layers were combined, neutralized withsaturated sodium hydrogencarbonate soltuion (5×70 mL), washed with brine(2×60 mL), dried over anhydrous sodium sulfate, filtered, concentratedin vacuo, and purified by silica gel flash chromatography(dichloromethane:methanol=50:1→20:1). Thereafter, the reaction productwas further purified by high performance liquid chromatography (ODScolumn, methanol:water=80:20)(yield: 3.3 mg (3.49 μmol), recovery:15.0%).

[0131]¹H NMR (300 MHz, CDCl₃+TMS); 5.16-5.14 (2H, br, —CH═CH—), 4.60(1H, br, H-1 (R and S)), 4.31-2.88 (11H, m), 2.17-2.13 (2H, br, OCOCH₂), 1.82-1.80 (4H, br, CH₂ —CH═CH—CH₂ ), 1.42 (2H, br, OCOCH₂CH₂ ), 1.11(20H, br, —CH₂ —), 0.72 (30H, m, CH₃ at t-Bu & CH₃ at Acyl), −0.08 (18H,br, Si—CH₃ )

[0132] Route j:3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-O-oleoyl-glycerol Sodium Salt(XI)

[0133] Into 7 mL of a solution of acetic acid, tetrahydrofuran,trifluoroacetic acid and water (3:1:0.4:1), 358.4 mg (378 mmol) of thecompound (X) was dissolved. The solution was reacted at room temperaturefor 16 hours while stirring, and the reaction mixture was extracted withethyl acetate (3×10 mL). The organic layers were combined, washed withbrine (2×20 mL), dried over anhydrous sodium sulfate, filtered,concentrated in vacuo, and purified by silica gel flash chromatography(dichloromethanemethanol=10:1→dichloromethane:methanol:water=65:25:4)(yield: 138.1 mg(229 mmol), recovery: 62.7%).

[0134]¹H NMR (300 MHz, CD₃OD+TMS); 5.24-5.17 (2H, m, —CH═CH—), 4.69 (1H,m, H-1 (R and S)), 4.18-2.75 (11H, m), 2.29-2.21 (2H, m, OCOCH₂ ),1.94-1.90 (4H, m, CH₂ —CH═CH—CH₂ ), 1.49 (2H, br, OCOCH₂CH₂ ), 1.20(20H, br, —CH₂ —), 0.78 (3H, t, J=6.3, CH₃ )

Example 2

[0135] The Steps h-j were carried out in the same manner as in Example 1except that myristoleic acid was used in place of oleic acid tosynthesize3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-o-myristoleoly-glycerolsodium salt (yield: 118.7 mg (217 mmol), recovery: 59.8%).

Example 3

[0136] The same procedure as in Example 2 was repeated except thatpalmitoleic acid was used in place of oleic acid to synthesize3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-O-palmitoleoyl-glycerolsodium salt (yield: 142 mg (247 mmol), recovery: 67.7%).

Example 4

[0137] The same synthesis example as in Example 1, except that thecompound (IX′ diester) was used in place of the compound (IX: monoester)in the route i of preparing the compound (X) from the compound (IX), anda molybdenum oxidizer was used in place of OXONE, will be described.

[0138] 13.1 mg (11.0 μmol) of the compound (IX′ diester) was dissolvedin 0.5 mL of dichloromethane and 0.5 mL of methanol. 50 μL of 0.06Msolution of hexaammonium heptamolybdate tetrahydrate ((NH₄)₆Mo₇O₂₄.4H₂O)in 30% hydrogen peroxide was further added thereto and stirred at roomtemperature for 50 hours. Thereafter, 10 mL of ethyl acetate was addedto the reaction solution, and the resultant solution was washed withsaturated sodium hydrogencarbonate solution (2×5 mL) and brine (2×5 mL),dried over anhydrous sodium sulfate, filtered, concentrated in vacuo,and purified by silica gel flash chromatography(dichloromethane:methanol=50:1→10:1). As a result, a colorless oilysubstance was obtained (yield: 7.8 mg (6.4 mmol), recovery: 58.2%).

[0139] The compound represented by General Formula (1) of the presentinvention was subjected to a physiological assay.

[0140] <Assay 1>

[0141] An assay on inhibitory effect against a DNA polymerase α wascarried out in the following manner. 0.05 U of a DNA polymerase αpurified and isolated from a bovine thymus by an immunoaffinity columnwas mixed with each of test compounds, sulfopyranosylacylglycerol(hereinafter, simply referred to as “SQAG”) derivatives, namely, SQAG 1,SQAG 2 and SQAG 3 (listed in table 1) dissolved in DMSO. Each mixturewas added with a buffer containing inorganic salts for the enzymaticreaction, [³H]-labeled dTTP and compounds for reaction containing atemplate DNA strand, and incubated at 37° C. for 60 minutes.

[0142] After the enzymatic reaction was quenched, the resultant reactionproduct was fixed on a dedicated filter and subjected to measurement bya liquid scintillation counter. The amount of enzymatically incorporateddTTP was calculated as a radiation dose (cpm) of [³H]. Note that, eachof the sulfopyranosylacylglycerol derivatives is a mixture of the S- andR-configurations with respect to an absolute configuration of the carbonof the 2-position of the glycerol moiety.

[0143] The results are shown as IC₅₀ in Table 1 below. TABLE 1Inhibitory activity on DNA polymerase α

DNA polymerase inhibitory activity Compound R₁₀₁ IC₅₀ (μg/mL) SQAG1CH₃˜(CH₂)₃˜(CH═CH—CH₂)₁—(CH₂)₆—CO— 9.0 (14:1) SQAG2CH₃—(CH₂)₅—(CH═CH—CH₂)₁—(CH₂)₆—CO— 5.5 (16:1) SQAG3CH₃—(CH₂)₇—(CH═CH—CH₂)₁—(CH₂)₆—CO— 2.0 (18:1)

[0144] As is clear from Table 1, the compounds subjected to the assayexhibit significant inhibitory activity against the DNA polymerase α.

[0145] Colon cancer cells and gastric cancer cells used in the followingtwo assays are only for the purpose of illustration of cancer cells forwhich the medicinally active agent of the present invention effectivelyworks. Thus, cancer cells for which the medicament of the invention iseffective are not limited to these. Examples of other cancer cellsinclude those of esophageal cancer, gastric cancer, colon cancer,including those at colon and recta, thyroid cancer, bladder cancer,kidney cancer, prostatic cancer, malignant lymphoma, brain tumor, lungcancer, laryngeal cancer, pharyngeal cancer, hepatic cancer, gallbladdercancer, bile duct cancer, pancreas cancer, breast cancer, uterinecancer, ovarian cancer, vaginal cancer, leukemia, childhood cancer, skincancer, osteosarcoma, tongue cancer, cancer of small intestine, penilecancer, urethral cancer, ureteral cancer, testicular cancer, thymoma andmyeroma.

[0146] <Assay 2>

[0147] An assay on anticancer activity against cultured colon cancercells was carried out in the following manner.

[0148] Colon cancer cells DLD-1 were maintained and subcultured in RPMI1640 medium (containing 10% calf serum). Each of the test compounds(SQAG 2, SQAG 3 shown in Table 1) was suspended and diluted in themedium, and then the cancer cells were cultivated together with themedium in a 96-well plate at 3×10³ cells/well. After 48 hourcultivation, the MTT assay (Mosmann, T: Journal of Immunological Method,65, 55-63 (1983)) was carried out to compare survival rates.

[0149] The results are shown in FIG. 1.

[0150] In FIG. 1, open squares connected by a solid line indicate SQAG2and open circles connected by a solid line indicate SQAG3.

[0151] As is clear from FIG. 1, all of the sulfopyranosylacylglycerolderivatives have significant anticancer activities against the coloncancer cells used.

[0152] <Assay 3>

[0153] An assay on anticancer activity against cultured gastric cancercells was carried out in the same manner as in the assay 2 except thatgastric cancer cells NUGC-3 were used instead of the colon cancer cellsDLD-1.

[0154] The results are shown also in FIG. 1.

[0155] In FIG. 1, solid squares connected by a solid line indicate SQAG2and solid circles connected by a solid line indicate SQAG3.

[0156] As is clear from FIG. 1, the sulfopyranosylacylglycerolderivatives have anticancer activities against the gastric cancer cellsused.

[0157] <Assay 4>

[0158] Tests for human cancer-cell implanted mice were conducted in thefollowing manner.

[0159] 5×10⁵ of human lung cancer cells A-549 cultured in an MEM mediumcontaining 5% calf serum were implanted in nude mice BALB/cAcl-nu. Thesize of the tumor formation site was periodically measured. When thesize of the tumor reached 30-50 mm³ (42 days after the implantation),the mice were subjected to an administration test.

[0160] Five mice were assigned at random to test groups and a controlgroup. A test compound (SQAG1, SQAG2 and SQAG3 listed in Table 1)suspended in PBS in a concentration of 100 μg/100 μL was administered tothe test groups, and PBS was administered to the control group at a doseof 100 μL, every 3 days. This administration operation was repeated 8times. The size of the tumor formation site was measured at all theadministration times. The volume of the tumor was calculated inaccordance with the following formula.

Volume of tumor=tumor-site length×(tumor site width)²×0.5

[0161] The results obtained for the test compounds are respectivelyshown in FIG. 2 (SQAG1), FIG. 3 (SQAG2) and FIG. 4 (SQAG3).

[0162] In each Figure, the horizontal axis represents days afterimplantation of the cancer-cell and the vertical axis represents thevolume of a tumor.

[0163] It was demonstrated that each of the test compounds significantlysuppresses the formation of the tumor, compared to the control group.

[0164] No particular change was observed in the state of mice in thetest groups at the aforementioned dose. The mice were alive in the samestate as in the control group.

[0165] <Assay 5>

[0166] 5×10⁵ of cultured lung cancer cells A-549 were subcutaneouslyinjected into each of 7 week-old female nude mice BALB/cAcl-nu having20-22 g weight, and the size of tumor was measured every 3 days from 37days after the implantation. At 43 days after the implantation when thesizes of the tumor in all of the tumor-bearing mice reach 25-35 mm³, themice were randomly divided into 7 groups of 4 mice for each. Of the 7groups, one is used as a control group. 100 μL of PBS was subcutaneouslyinjected into the mice of the control group. To the remaining 6 groups,SQAG1 (14:1), SQAG2 (16:1) and SQAG3 (18:1) were subcutaneously injectedby dissolving each of the test compounds in 100 μL of PBS so as to givedoses of 4 mg and 20 mg per 1 kg weight. The injection was performedevery 3 days. This administration operation was repeated from 43 days to64 days after the cancer-cell implantation. The size of the tumor wasmeasured every 3 days until 70 days after the implantation. The volumeof the tumor was calculated in the same manner as in Assay 4.

[0167] The results obtained for the test compounds are respectivelyshown in FIG. 5 (SQAG1), FIG. 6(SQAG2) and FIG. 7 (SQAG3).

[0168] In each of the test groups, it was demonstrated that theformation of the tumors is significantly suppressed compared to thecontrol group.

[0169] After completion of the test, major organs, such as lung, heart,stomach, liver, pancreas, kidney, intestine and brain, of all the miceof each administration group were subjected to pathological evaluation,and no pathologically abnormality was observed in any organ.

[0170] As explained in the foregoing, according to the presentinvention, there is provided a medicament containing at least onecompound selected from the group consisting ofsulfopyranosylacylglycerol derivatives represented by General Formula(1) and pharmaceutically acceptable salts thereof, as an activeingredient.

[0171] Additional advantages and modifications will readily occur tothose skilled in the art. Therefore, the invention in its broaderaspects is not limited to the specific details and representativeembodiments shown and described herein. Accordingly, variousmodifications may be made without departing from the spirit or scope ofthe general inventive concept as defined by the appended claims andtheir equivalents.

What is claimed is:
 1. A method for treating a cancer excludingadenocarcinoma, the cancer being selected from the group consisting ofepithelioma, glioma, sarcoma, melanoma, lymphoma and leukemia,comprising administering to a subject in need thereof and suffering fromsaid cancer, a pharmaceutically effective amount of at least onesulfoquinovosylacylglycerol compound represented by formula (1):

 wherein R₁₀₁ represents an acyl residue of an unsaturated higher fattyacid, and R₁₀₂ represents a hydrogen atom, and/or at least onepharmaceutically acceptable salt thereof.
 2. The method according toclaim 1, wherein said R₁₀₁ of formula (1) is represented by formula:R—C(═O)—wherein R is a straight-chain aliphatic unsaturated hydrocarbongroup having 13-25 carbon atoms and including 1-6 unsaturated bonds. 3.The method according to claim 2, wherein for R, the number of carbonatoms is selected from odd numbers from the group consisting of 13, 15,17, 19, 21, 23 and
 25. 4. The method according to claim 3, wherein R₁₀₁of formula (1) is CH₃—(CH₂)₃—(CH═CH—CH₂)—(CH₂)₆—CO—.
 5. The methodaccording to claim 3, wherein R₁₀₁ of formula (1) isCH₃—(CH₂)₅—(CH═CH—CH₂)—(CH₂)₆—CO—.
 6. The method according to claim 3,wherein R₁₀₁ of formula (1) is CH₃—(CH₂)₇—(CH═CH—CH₂)—(CH₂)₆—CO—.
 7. Themethod according to claim 1, wherein the cancer is epithelioma.
 8. Themethod according to claim 1, wherein the cancer is glioma.
 9. The methodaccording to claim 1, wherein the cancer is sarcoma.
 10. The methodaccording to claim 1, wherein the cancer is melanoma.
 11. The methodaccording to claim 1, wherein the cancer is lymphoma.
 12. The methodaccording to claim 1, wherein the cancer is leukemia.
 13. A method fortreating an adenocarcinoma cancer excluding colon cancer, lung cancerand gastric cancer, comprising administering to a subject in needthereof and suffering from said adenocarcinoma cancer, apharmaceutically effective amount of at least onesulfoquinovosylacylglycerol compound represented by formula (1):

 wherein R₁₀₁ represents an acyl residue of an unsaturated higher fattyacid, and R₁₀₂ represents a hydrogen atom, and/or at least onepharmaceutically acceptable salt thereof.
 14. The method according toclaim 13, wherein said R₁₀₁ of formula (1) is represented by formula:R—C(═O)— wherein R is a straight-chain aliphatic unsaturated hydrocarbongroup having 13-25 carbon atoms and including 1-6 unsaturated bonds. 15.The method according to claim 14, wherein for R, the number of carbonatoms is selected from odd numbers from the group consisting of 13, 15,17, 19, 21, 23 and
 25. 16. The method according to claim 14, whereinR₁₀₁ of formula (1) is CH₃—(CH₂)₃—(CH═CH—CH₂)—(CH₂)₆—CO—.
 17. The methodaccording to claim 14, wherein R₁₀₁ of formula (1) isCH₃—(CH₂)₅—(CH═CH—CH₂)—(CH₂)₆—CO—.
 18. The method according to claim 14,wherein R₁₀₁ of formula (1) is CH₃—(CH₂)₇—(CH═CH—CH₂)—(CH₂)₆—CO—.